tbuckley/cabot-search huggingface dataset:
A classification system for urothelial carcinoma (UC) defined by genomic drivers and the tumor microenvironment (TME) is predictive of immunotherapy response.
Authors: Konstantin Chernyshov, Natalia Miheecheva, Anna Love, Krystle Nomie, Nathan Fowler, Felix Frenkel
Journal: Journal of Clinical Oncology (2022)

4591 Background: UC is associated with high recurrence rates, progression, and resistance to platinum-based therapy. Checkpoint inhibitors (CPIs) are often used for treating UC, but predictive biomarkers that characterize response are lacking in the majority of patients. Defining the TME is essential to understanding patient response to CPIs. Employing a transcriptome-based classification platform, we sought to identify predictive and prognostic subtypes of UC using malignant cell and TME features. Methods: We collected a metacohort of 2,418 UC samples from 14 publicly available datasets, one of which had atezolizumab response data (IMvigor210). Using the methodology described in Bagaev et al. 2021, we selected 28 signatures composed of specific gene sets reflecting distinct cellular processes. Analysis of signature expression and unsupervised clustering was performed. Results: We identified 7 recurring novel UC subtypes (Table 1) with unique genomic and molecular characteristics. The subtypes and key findings include: an immune desert (D) subtype characterized by genomic instability high HER2 expression; an immune desert, FGFR-altered (D-FGFR) subtype with FGFR alterations; an immune enriched (IE) subtype with an enriched TME and high CPI response; a fibrotic (F) subtype with a mesenchymal TME, and strong TGFβ signaling; an immune enriched, fibrotic (IE-F) subtype with a mixed TME and a high CPI response rate; a fibrotic, basal (F-B) subtype with a mesenchymal TME and minimal genomic targets, and a neuroendocrine-like (NE-L) subtype with a high CPI response rate. Conclusions: UC can be classified into 7 subtypes with distinct prognoses, CPI response rates, and druggable targets using malignant cell and TME profiling. Patients with IE, IE-F, and NE-L UCs may be good candidates for CPIs. D UCs may benefit from HER2-i and PARP-i, while FGFR-i might be more suitable for D-FGFR UCs. TGFβi and PARPi may be effective for F UCs, but F-B UCs have no targetable findings. These findings warrant additional investigation for clinical translation. [Table: see text]
Survival trends in hilar and extrahepatic cholangiocarcinoma based on Facility type: A National Cancer Database analysis.
Authors: Faith Abodunrin, Joshua Eyitemi, Shalini Jain, Connor Tupper, Peter T. Silberstein, Vincent Eaton
Journal: Journal of Clinical Oncology (2022)

e13536 Background: The diagnosis and treatment of Cholangiocarcinoma continues to pose a challenge. Due to their rarity, few studies have examined the impact of facility type on the survival of patients with extrahepatic cholangiocarcinoma. The hypothesis of this study was that differences in the outcome of patients at different facility types exist. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with hilar and extra-hepatic cholangiocarcinoma from 2004 to 2017 using ICD-O-3 histology codes. We used four different cohorts to assess survival amongst those at different facility types: academic/research programs, community cancer programs, comprehensive community center programs, and integrated network cancer programs. Data was analyzed and descriptive statistics and Kaplan Meier curves were produced using SPSS to measure survival in these patients with statistical significance set at α = 0.05. Results: Using the database, a total of 57,146 patients with hilar and extrahepatic cholangiocarcinoma were identified. Overall median survival in these patients was 11.2 months. Patients at Academic/research programs had a median survival of 14 months (95% CI 14.1-14.8 p &lt; 0.001). In comparison, median survival of 9.7 months (95%CI 9.3-10.2 p &lt; 0.001) and 8.7 months (95% CI 8.4-8.9 p &lt; 0.001) was noted in Integrated network and Comprehensive community cancer programs, respectively. Community cancer programs had the lowest median survival rate in patients with all extrahepatic biliary tract cancers included in our study was 6.9 months (95% CI 6.4-7.7 p &lt; 0.001). Specifically, patients with Klatskin tumors at Academic/Research programs had median survival of 10.3 months (95% CI 8.6-11.9 p &lt; 0.0010) compared to median survival of 3.6 months in patients treated at Community Cancer program. We also studied specific histology types such as papillary and mucinous adenocarcinomas. In papillary adenocarcinomas, there are no statistically significant differences in median survival in different facility types. In mucinous adenocarcinomas, median survival of 26.5 months was found in academic/research program patients compared to 16.2 months in Comprehensive Community Cancer program patients (p &lt; 0.001). Conclusions: Median overall survival in patients with hilar and extrahepatic cholangiocarcinoma was significantly higher in academic/research programs compared to other facility types. Further studies are needed to ascertain why academic/research programs have superior outcomes in these patients.
Early safety and efficacy from a phase I open-label clinical study of LVGN7409 (CD40 agonist antibody) in patients with advanced or metastatic malignancies.
Authors: Siqing Fu, Andrae Lavon Vandross, Yi Hsin Hsu, Naiyi Shi, Lynn Jiang, Fusheng Su, Jieyi Wang, C. Hubert Chan
Journal: Journal of Clinical Oncology (2022)

e14501 Background: LVGN7409 is a recombinant monoclonal antibody against CD40. The modified Fc fragment binds FcγRIIB selectively. LVGN7409 activates CD40 in Fc-FcγRIIB cross-link dependent manner and thus optimally in CD40 and FcγRIIB enriched tumor microenvironment. LVGN7409 demonstrated more robust antitumor efficacy and superior safety profile than published CD40 agonist antibodies in preclinical models. An open-label, first in human phase 1 study of LVGN7409 as a single agent, combined with LVGN3616 (anti-PD-1 antibody), and combined with LVGN3616 and LVGN6051 (CD137 agonist antibody) is ongoing. Methods: LVGN7409 was given intravenously every 3 weeks. For single agent dose-finding, LVGN7409 accelerated doses from 0.01 to 0.1mg/kg, and then conventional “3 + 3” design from 0.3 mg/kg. The objectives evaluate LVGN7409 safety, RP2D in a single agent and combination therapy, PK, immunogenicity, preliminary antitumor activity, and exploratory PD biomarkers. Results: As date on January 24, 2022, 12 patients (5 males, 7 females; median age 56, range 29-76; all ECOG 1 at screening; median 6 lines of prior therapies, range 2-14) have been treated with LVGN7409 monotherapy into 6 cohorts (0.01-0.03mg/kg n=1, 0.1-0.3mg/kg n=3, 1mg/kg n=6, 2mg/kg n=2). They received a median of 3 (range 1-10) treatment cycles. No DLT event was observed up to 2mg/kg of LVGN7409. Treatment-related adverse events (TRAEs) of any grade occurred in 10 out of 12 patients (n=10) including infusion related reaction (n=7), amylase increased (n=5), lipase increased (n=5), ALT increased (n=5), AST increased (n=5), bilirubin increased (n=1), WBC or neutrophil decreased (n=1), nausea (n=1), and cytokine release syndrome (n=1). Two patients experienced grade 3 TRSAEs: amylase/lipase increased (n=1) and ALT/AST increased (n=1). Most TRAEs were transient, asymptomatic, self-limited, and occurred in the initial cycle without recurrence upon rechallenge. Four of nine evaluable patients (44%) hadstabledisease by RECIST1.1 and iRECIST, with one active patient being treated for more than 8 months. CD40 receptor occupancy was achieved at the dose of 0.3 mg/kg and above; preliminary pharmacodynamic marker changes were observed. Conclusions: Preliminary evidence showed LVGN7409 monotherapy was well tolerated up to 2mg/kg. Approximately 44% of stable diseases were observed in these heavily treated patients. The favorable safety profile and preliminary antitumor activity warrant further evaluation of LVGN7409 as a single agent and in combination with other cancer therapeutics in patients with advanced malignancies. Clinical trial information: NCT04635995.
Total neoadjuvant treatment approach and carcinoembryonic antigen level in locally advanced rectal cancer.
Authors: Ashish Sethi, Stephen Abel, Rodney E. Wegner, Paul Renz, Alexander V. Kirichenko, Patrick Wagner, James McCormik, Gene Grant Finley, Moses S. Raj
Journal: Journal of Clinical Oncology (2022)

e15595 Background: Total Neoadjuvant therapy (TNT) has gained acceptance in the treatment of locally advanced rectal cancer, although the optimal sequencing of therapy chemoradiation (CRT) followed by consolidation chemotherapy (cChT) or induction chemotherapy followed by chemoradiation (iChT), remains a subject of ongoing debate. The effect of TNT sequencing and carcinoembryonic antigen (CEA) level on progression free survival (PFS) is uncertain. We conducted a retrospective analysis to examine these issues. Methods: Patients (n = 44) with locally advanced rectal cancer from June 2016 to December 2020 were reviewed. CEA level was compared against the primary outcome of response to TNT approaches. We categorized patients into 3 groups based on pre-TNT and post-TNT (i.e. pre-surgical) CEA: normal CEA PRE/ normal CEA POST , elevated CEA PRE /normal CEA POST , elevated CEA PRE /elevated CEA POST. 3-Year PFS was calculated using Kaplan-Meier method. Univariable and multivariable logistic regression analyses identified characteristics predictive of PFS and clinicopathologic variables associated with TNT sequencing. Results: The study cohort had a median age of 61 years and was predominantly male (70%) and Caucasian (94%). Pre-treatment stage was either II (27%) or III (72%), with the majority (65%) undergoing iChT. Downstaging occurred in 42/44 (95%). Baseline CEA was elevated in 40.9% of patients. On multivariable, logistic regression variable associated with receipt of CRT followed by cChT included: Age &gt; 61 years clinical T4 disease and lack of T downstaging (p &lt; 0.05 for all).There was no difference in 3-year PFS between patients receiving iChT versus patients receiving cChT (p = 0.53). When patients were stratified according to pretreatment CEA level, no difference in 3 year PFS were noted (p = 0.46). On multivariable analysis, lack of nodal downstaging following neoadjuvant treatment was associated with higher likelihood of progression (p = 0.02). Similarly, pretreatment CEA &gt; 4.25 ng/ml (p = 0.08) and failure of CEA to decrease by &gt;2 ng/ml following TNT (p = 0.07) trended toward higher likelihood of progression. Conclusions: Neither TNT sequencing, nor baseline CEA predicted the PFS although the power of our study was limited. Lack of nodal downstaging was identified as a predictor of worse PFS. Further areas of study should include plasma-based assays to quantitate circulating tumor DNA and next generation sequencing to assess prognosis with different sequencing of TNT.
High-dose icotinib in advanced lung adenocarcinoma(LUAD) patients harboring EGFR exon 21 L858R mutation: Real-world (RW) experience in a single center.
Authors: Yixuan Yu, Huijing Dong, Yumin Zheng, Zhening Liu, Huijuan Cui
Journal: Journal of Clinical Oncology (2022)

e21036 Background: Non-small cell lung cancer(NSCLC) patients(pts) with epidermal growth factor receptor (EGFR) exon 19 deletion have more benefit from EGFR-tyrosine kinase inhibitors(EGFR-TKIs) compared to pts with EGFR exon 21 L858R mutation. Icotinib, which is a first-generation EGFR-TKI had been approved for use in EGFR-positive advanced NSCLC pts. A phase II trial(INCREASE trial) showed that high-dose icotinib 250mg tid(ico250) can effectively prolong the progression-free survival(PFS) of NSCLC pts with exon 21 L858R mutation without increased toxicity. However, the RW evidence is lacking. Methods: In this single-center, single-arm study, data were retrospectively collected from China-Japan Friendship Hospital. Pts with advanced LUAD, harboring EGFR exon 21 L858R mutation, and who received ico250 for more than 20 days without chemotherapy or immunotherapy were reviewed. Clinical data were analyzed for PFS, objective response rate(ORR), disease control rate(DCR), overall survival(OS), duration of treatment(DoT) and adverse events(AEs). Survival factors were evaluated by univariate and multivariate Cox regression analysis. Results: In total 40 pts(14M,26F; median age 67[46-86]; smoker:20.0%; ECOG performance status 0-1/2-3: 33/7) who received ico250 between 4/2019-11/2021 were analyzed. The median line of pre-ico therapies was 1(range 0-2). At the cut-off day, 29(72.5%) pts had discontinued ico250, and 7(17.5%) pts died. Overall, ORR was 30.0%, DCR was 80.0%, median DoT was 8.0mos (95%CI, 3.4-12.6), median PFS was 12.9mos (95%CI, 8.2-17.6) and median OS was not reached. The univariate and multivariate analysis showed that there was no significant and independent factor associated with PFS(all P&gt; 0.05). 30(75.0%) pts experienced AEs, while the most common AEs were rash(24,60.0%), dry skin(9,22.5%), paronychia(8,20.0%) and diarrhea(6,15.0%). Grade 3/4 AEs in 6(15.0%) pts included AST/ALT elevation(3,7.5%), rash(2,5%), diarrhea(1,2.5%) and mucositis(1,2.5%)(1 suffered both rash and mucositis). 5(12.5%) pts discontinued high-dose icotinib due to AEs. Conclusions: These data add to the RW evidence that the efficacy and tolerability of ico250 in advanced LUAD pts harboring EGFR exon 21 L858R mutation. The efficacy results are consistent with the previous INCREASE trial. High-dose icotinib could be considered whatever the previous treatment and basic characteristics of LUAD pts with exon 21 L858R mutation. However, the higher incidence of grade3/4 AEs deserves special attention.
Cost-effectiveness of waiving coinsurance for follow-up colonoscopy after a positive stool-based colorectal screening test in a Medicare population.
Authors: A. Fendrick, David A. Lieberman, Vahab Vahdat, Jing Voon Chen, A. Burak Ozbay, Paul J. Limburg
Journal: Journal of Clinical Oncology (2022)

e13624 Background: Commercial insurance plans are required to cover, with no patient cost sharing, a follow-up colonoscopy (COL) after a positive stool-based colorectal cancer (CRC) screening test. Medicare beneficiaries may still be responsible for 20% coinsurance for a follow-up COL, posing a financial barrier to screening completion. Removing the coinsurance may increase screening adherence and improve outcomes. The estimated cost-effectiveness of stool-based CRC screening was compared among adherence scenarios that assumed the status quo (20% coinsurance for follow-up COL) or waived follow-up COL coinsurance. Methods: The CRC-AIM microsimulation model simulated US Medicare beneficiaries undergoing stool-based CRC screening between ages 65-75 years. Outcomes of total costs, total quality adjusted life years (QALYs), life-years gained (LYG), CRC incidence reductions (IR), and CRC mortality reductions (MR) were calculated per 1000 individuals versus no screening using the weighted average of the outcome with multitarget stool DNA, fecal immunochemical test, and fecal occult blood test, scaled by their estimated use. Costs of follow-up COL were assumed to have 20% coinsurance in the status quo scenario. Four comparative scenarios assumed that waiving coinsurance increased published, real-world stool-based screening or follow-up COL adherence rates by 5% or 10%. Results: In scenarios where waiving coinsurance was assumed to increase screening and/or follow-up COL adherence, up to 21 more LYG and greater IR and MR were observed vs the status quo (Table). Total costs in waived coinsurance scenarios (≥$6,398) were comparable to the status quo ($6,449) as the cost savings in CRC care offset the increased COL costs. Total QALYs in waived coinsurance scenarios (≥9.3671) were greater than the status quo (9.3643) because of improved clinical outcomes. Stool-based testing in waived coinsurance scenarios was either dominant (more effective and less costly) or cost-effective at $50,000/QALY with minimal incremental costs vs the status quo. Conclusions: In a simulated Medicare population, clinical CRC outcomes improved and stool-based screening was cost-effective or cost-saving when waiving the 20% coinsurance was assumed to modestly (5%) increase adherence rates for total CRC screening and/or a COL following a positive test. [Table: see text]
IMMUNIB trial (AIO-HEP-0218/ass): A single-arm, phase II study evaluating safety and efficacy of immunotherapy nivolumab in combination with lenvatinib in advanced-stage hepatocellular carcinoma (HCC).
Authors: Arndt Vogel, Gabriele Margareta Siegler, Jurgen Siebler, Udo Lindig, Michael Schultheiß, Tobias Müller, Henry Simon, Christiane Jöckel, Daniel Wilhelm Mueller, Salah-Eddin Al-Batran, Anna Saborowski, Enrico N De Toni
Journal: Journal of Clinical Oncology (2022)

4107 Background: The field of systemic options in HCC therapy has significantly evolved in recent years, and first line options now include sorafenib, lenvatinib and bevacizumab plus atezolizumab. Nivolumab is a recombinant human IgG4 mAb targeting PD-1 with clinically meaningful activity in about 15-20% of HCC patients, but the confirmatory phase III trial Checkmate 459 failed to demonstrate superiority over sorafenib. VEGF signaling is not only a driver of tumor angiogenesis, but also contributes to the formation of an immunosuppressive microenvironment. Combinations of anti-angiogenic multikinase inhibitors, specifically lenvatinib, and PD-1/PD-L1 inhibitors have demonstrated remarkable antitumor activity and manageable toxicity in several tumor types, including HCC. We therefore aimed to evaluate the efficacy of nivolumab in combination with lenvatinib as first line treatment in patients with advanced HCC. Methods: This investigator-initiated single-armed phase II trial (NCT03841201) recruited 50 patients (pts) at 8 sites in Germany between 07/2019 and 05/2021. Primary endpoints were objective response rate (ORR) according to investigator assessed RECIST 1.1 and safety/tolerability. Secondary endpoints included ORR according to iRECIST, time to progression (TTP), progression free survival (PFS) and overall survival (OS). Recruitment of the trial was completed in 05/2021. At the time of analysis, 4 patients remained on treatment. Results: 50 pts (24 BCLC B, 24 BCLC C, 2 not evaluable) were enrolled and received at least one dose of the combination treatment. ORR by RECIST 1.1 was 28% (CR: 6.0%, PR: 22.0%, SD: 46.0%, PD: 12.0%). Median PFS was 9.0 mo (26 events). Median TTP was 11.5 mo (0.69 at 6 mo, 0.45 at 12 mo, 0.36 at 18 mo) and median OS was 27.1 mo (8 events). 45 (91.8%) pts experienced at least one TRAE, of which 29 pts (59.1%) encountered at least one TRAE ≥ grade 3. 17 (34.7%) pts had one or more SAE related to the study medication, whereof 15 pts (30.6%) experienced at least one treatment related SAE ≥ grade 3. Conclusions: No new safety signals were observed for the combination of nivolumab and lenvatinib. Although the study failed to reach its prespecified ORR of at least 40%, the high activity in all efficacy endpoints with a mOS of 27.1 mo supports the further investigation of the combination in HCC. Clinical trial information: NCT03841201.
Impact of activating androgen receptor (AR) mutations on AR sensitivity to alternative ligands and response to ODM-208, a selective, first-in-class CYP11A1 inhibitor, in patients with advanced metastatic castration-resistant prostate cancer (mCRPC).
Authors: Alice Bernard-Tessier, Tapio Utriainen, Natalie Cook, Philippe Barthélémy, Nada Lallous, Martin Gleave, Tarja Ikonen, Reetta Riikonen, Pasi Pohjanjousi, Chris Garratt, Karim Fizazi
Journal: Journal of Clinical Oncology (2022)

5057 Background: Activating AR mutations ensure a continued AR activation by non-androgen steroid ligands, e.g. progesterone and glucocorticoids. CYP11A1 is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone, from which all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids) are subsequently derived. ODM-208, an oral, selective inhibitor of CYP11A1, is being evaluated for safety and efficacy as a treatment of mCRPC in the ongoing CYPIDES phase I/II trial in men previously treated with both novel hormonal therapies and taxanes (ClinicalTrials.gov identifier: NCT03436485). Preliminary phase 1 results were previously reported (Fizazi K et al., ASCO GU 2022). Here we confirm that the in-vitro sensitivity of common AR mutations to ODM-208 treatment is mirrored in patient response in CYPIDES phase 1. Methods: ODM-208 was administered at daily doses between 6-150 mg (phase 2 dose: 10 mg) with dexamethasone and fludrocortisone, resulting in maximal suppression in all measured steroids at all doses. AR ligand-binding domain (LBD) mutations (L702H, V716M, W742L, W742C, H875Y, F877L, T878A, T878S, M896T, M896V) were assessed using a BEAMing assay (Sysmex Inostics) from plasma circulating cell-free DNA (cfDNA) collected before the first dose of ODM-208. The activation of wild-type (wt) and LBD mutated AR with various ligands was also studied in vitro using a luciferase reporter assay in AR negative PC3 cells. Results: 17 of 44 patients had at least one AR activating mutation, the most frequent being L702H (n = 11), T878A (n = 10), and H875Y (n = 6). Eleven out of the 16 evaluable patients (68%) with an AR LBD mutation achieved ≥50% reduction in serum PSA compared with 2 out of the 24 evaluable patients (8%) without an AR LBD mutation (P &lt;.0001). The in vitro sensitivity of each of these common AR mutations to a variety of non-androgenic steroids will be presented, along with detailed PSA responses, duration of responses, and safety in mCRPC patients bearing the same mutations. Conclusions: AR activating mutations may permit continued hormone dependence in mCRPC, related to actions of non-androgenic steroid hormones. Treatment with ODM-208 blocked all steroid hormone production and resulted in frequent ≥50% PSA reductions in this group of heavily pretreated mCRPC pts with various AR LBD mutations, some being long-lasting. cfDNA AR mutations are a promising predictive biomarker for ODM-208 efficacy. Dexamethasone did not activate mutated ARs, supporting its selection for glucocorticoid replacement therapy in combination with ODM-208. Clinical trial information: NCT03436485.